(Hypertension. 1999;34:983-986.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Low-Dose Angiotensin II Increases Free Isoprostane Levels in Plasma
From the Department of Physiology and Biophysics, Mayo School of Medicine and Mayo Clinic, Rochester, Minn.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Chronic intravenous infusion of subpressor doses of angiotensin II causes blood pressure to increase progressively over the course of several days. The mechanisms underlying this response, however, are poorly understood. Because high-dose angiotensin II increases oxidative stress, and some compounds that result from the increased oxidative stress (eg, isoprostanes) produce vasoconstriction and antinatriuresis, we tested the hypothesis that a subpressor dose of angiotensin II also increases oxidative stress, as measured by 8-epi-prostaglandin F2
(isoprostanes), which
may contribute to the slow pressor response to angiotensin
II. To test this hypothesis, we infused angiotensin II (10
ng/kg per minute for 28 days via an osmotic pump) into 6 conscious
normotensive female pigs (30 to 35 kg). We recorded mean
arterial pressure continuously with a telemetry system and
measured plasma isoprostanes before starting the
angiotensin II infusion (baseline) and again after 28 days
with an enzyme immunoassay. Angiotensin II infusion
significantly increased mean arterial pressure from 121±4
to 153±7 mm Hg (P<0.05) without altering total
plasma isoprostane levels (180.0±24.3 versus 147.0±29.2 pg/mL;
P=NS). However, the plasma concentrations of free
isoprostanes increased significantly, from 38.3±5.8 to 54.7±10.4
pg/mL (P<0.05). These results suggest that subpressor
doses of angiotensin II increase oxidative stress, as
implied by the increased concentration of free isoprostanes, which
accompany the elevation in mean arterial pressure
elevation. Thus, isoprostane-induced vasoconstriction and
antinatriuresis may contribute to the hypertension induced by the slow
pressor responses of angiotensin II.
Key Words: kidney • oxidative stress • prostaglandins • lipid peroxidation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The fast pressor effect of angiotensin II, induced by an intravenous bolus injection, is characterized by a rapid elevation of blood pressure, reaching a maximal increase of blood pressure in 1 to 2 minutes.1 2 This effect is due to an arterial vasoconstriction. However, the mechanism responsible for the progressive increase in blood pressure with long-term administration of subpressor doses of angiotensin II3 (slow pressor response) remains undefined.4 Several processes have been implicated in mediating this response, but none of them appears to completely account for this phenomenon.5 6 7 8 More recently, it has been shown that angiotensin can stimulate superoxidation (O2), which may quench nitric oxide (NO) with the formation of strong oxidative compounds such as peroxynitrite (ONOO-).9 10 Under these conditions, ONOO- could oxidize arachidonic acid, releasing isoprostanes.11 12 Among these substances, the 8-isoprostaglandin F2
is
considered the most ubiquitous and reliable index of oxidative
stress.
Isoprostanes are not only reliable markers of oxidative stress but also
possess intrinsic vasoconstrictor and
antinatriuretic properties via specific
receptors,11 12 raising the possibility that they
contribute to the hypertensive effects of angiotensin II.
If subpressor doses of angiotensin II also induce oxidative
stress, consequently increasing isoprostane levels, then it is possible
that the increases in isoprostanes are responsible, at least in part,
for the slow pressor responses to angiotensin II.
Therefore, in the present study we determined whether swine also
develop slow responses to subpressor doses of angiotensin
II and whether these responses are accompanied by an increase in
oxidative stress, as expressed by the elevation of plasma isoprostane
F2.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study, which had approval of the Institutional Animal Care and Use Committee, was performed in 6 female pigs with an average body weight of 35±3 kg. The major reason for conducting these studies in pigs resides in the anatomic similarity of the renal system with humans. The animals had free access to water and were fed chow containing 0.19% sodium. The pigs were fasted 16 hours before surgery and then anesthetized with 150 mg of xylazine and 1 g of ketamine; anesthesia was supplemented during surgery if necessary.
Blood Pressure Measurements
Blood pressure was monitored via a Physiotel telemetry implant
(Data Sciences International) placed in the ventral aspect of
the neck. Implants use a fluid-filled catheter, which refers pressure
from the catheter tip, inserted into the carotid artery, to a sensor
located in the body of the implant. The implant transmits the blood
pressure data telemetrically to a receiver that converts the
radiofrequency signal to a PC-based data collection system. This
allowed for blood pressure monitoring from conscious, freely moving
laboratory animals 24 hours a day for 7 control and 28
angiotensin II–infused days.
Angiotensin II Infusions
After 7 days of baseline blood pressure measurements, the pigs
were anesthetized, and a blood sample was withdrawn from the
jugular vein for plasma isoprostane levels. Under sterile conditions,
an osmotic pump with 2-mL capacity and of 4 weeks' duration was
implanted subcutaneously in the ventral aspect of the neck (model 2
ML4, Alza Corp). A polyethylene catheter connected to 1 end of the
osmotic pump flow modulator was inserted into the jugular vein. The
pump was primed with 20 mg of angiotensin II
(Asp-Arg-Val-Tyr-Ile-His-Pro-Phe acetate salt) (Sigma) in 2 mL
of sterile isotonic saline. Infusion occurred at a constant rate of 2.5
µL/h, which delivers 
14 ng/kg per minute at the beginning of the
study and 8 ng/kg per minute at the end of the study (because of the
growth of the pig). At the end of 28 days, the pigs were
anesthetized, and a blood sample was withdrawn from the jugular
vein for determination of plasma isoprostane levels. Isoprostanes
circulate in 2 distinct forms, esterified in LDL phospholipids and as
the free acid.13 14
Isoprostane Assay Procedure
Extraction and enzyme immunoassay procedures used to measure
isoprostanes follow the methods supplied in the kit provided by Cayman
Chemical with a few modifications. Plasma isoprostanes exist in
circulation as either a free base or esterified to lipoproteins. To
measure the esterified isoprostanes, a further extraction hydrolysis
step is required for conversion to free bases that can then be measured
by extraction and enzyme immunoassay. This measurement of all
isoprostanes is referred to as the total. Samples are removed from
-80°C storage and thawed on ice. Of the sample, 1.0 mL is used for
measurement of free isoprostanes, while 0.5 mL is used to measure total
isoprostanes. Absolute methanol is first added to all samples, followed
by thorough mixing and centrifugation. For free
isoprostane, the eluent is poured into a water/buffer solution and kept
on ice, while the total eluent is poured in a solution of 15% KOH and
incubated for 1 hour at 38°C. After incubation, a water/buffer
solution is also added to the total samples, with a pH of 3.1±0.5 in
all samples. Extraction is then performed on a Sep-Pak C18 column, with
washes of water and hexane. The isoprostanes are eluted from the column
with a solution of 99%/1% ethyl acetate/methanol, which is then dried
off under nitrogen, and the samples are reconstituted into a 1.0-mL
assay buffer. For the assay, standards and samples are first added in
triplicate to the 96-well plate provided in the kit, followed by
addition of tracer and antibody and then incubation overnight at room
temperature. The next day, the plate is washed several times with wash
buffer, followed by addition of Ellman's reagent. After optimal
development of color, the plate is read at 405 nm, and values of
unknowns are expressed as picograms per milliliter.
Data Analysis
Data are expressed in absolute values ±SEM. Paired t
tests were used to examine whether the isoprostane and blood pressure
levels were different before and after chronic infusion of
Angiotensin II. The control mean arterial
pressure (MAP) was the average of the last control day (day 7). The
paired comparison was made with the 28th day of angiotensin
II infusions, the same day the plasma isoprostane levels were
determined. When the normality test failed, the Wilcoxon rank
sum test was used instead. For all analyses, P<0.05
was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The effects of subpressor angiotensin II infusion on MAP are depicted in Figure 1. Infusion of angiotensin II increased MAP by day 2 of angiotensin II infusion. The increase plateaued on day 3 but appeared to increase again on day 15 and remained at an elevated level throughout the experiment. The MAP was 121±4 mm Hg on control day 7 and increased to 153±7 mm Hg (P<0.05) by day 28 of angiotensin II infusion. Figure 2 summarizes the plasma free isoprostane data. Plasma free isoprostane increased from 38.3±5.8 pg/mL on control day 1 to 54.7±10.4 pg/mL (P<0.05) on day 28 of angiotensin II infusion. Total plasma isoprostane levels were 180.0±24.3 pg/mL in control and 147.0±29.2 pg/mL on day 28 (P=NS).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Slow Responses to Angiotensin II
The results of the present study show that chronic intravenous administration of subpressor doses of angiotensin II produces, in swine, a progressive elevation of MAP that resembles all the characteristics of the slow pressor response. In fact, preliminary studies in 5 pigs showed that acute infusion of 10 ng/kg per minute angiotensin II for 1 hour increased plasma levels of free isoprostanes by 28% (P<0.09) and total isoprostanes by 29% (P<0.07), accompanied by a 4-mm Hg increase in MAP. This elevation of MAP is much smaller than the total increase of 32±3 mm Hg recorded after 28 days of infusion of 10 ng/kg per minute during chronic infusion. Another characteristic of the slow response to angiotensin II is that it takes at least 3 to 4 days to develop completely.15 Our results show that from day 1 of the infusion, there was a continuous increase of MAP from 121 to 135 mm Hg. On day 3, the blood pressure plateaued up to day 13. However, on day 15, there was a further increase of MAP, reaching 153±7 mm Hg on day 28. It should be noticed that on day 28, there was no indication that the increase of blood pressure had reached a plateau. The experiment was stopped at this time, however, because a new osmotic pump would have to be implanted to continue with the infusion of angiotensin. These results allow us to conclude that the continuous administration of 10 ng/kg per minute of angiotensin II, which does not increase MAP when given as an acute infusion (J.C. Romero et al, unpublished data, 1999), is capable of producing a marked increase in blood pressure of 32.5 mm Hg after 28 days of infusion. It remains undefined whether an infusion of 10 ng/kg per minute of angiotensin would have produced a greater increase in blood pressure if given for a longer period of time. These results are comparable to those obtained in rabbits,3 rats,1 2 7 8 and dogs.5 15
The mechanism underlying the slow response to angiotensin II remains undefined. However, it has been linked by other investigators to the level of sodium intake,5 sympathetic activation at the central nervous system,3 and arteriolar hypertrophy.15 A high sodium diet potentiates significantly the development of the slow response to angiotensin.5 From these observations, it has been concluded that the level of angiotensin in plasma during continuous infusion may be inappropriate with respect to the levels of extracellular fluid volume. This possibility has been discarded by some authors because the slow responses to angiotensin II are triggered by levels of angiotensin II that are below those that are usually needed to stimulate steroidogenesis or thirst. However, since angiotensin II itself has powerful natriuretic actions5 or, alternatively, it may stimulate antinatriuretic compounds (eg, isoprostanes), it is still possible that an alteration in the balance between the extracellular fluid volume and angiotensin levels may contribute to the hypertension.
The second possibility is that angiotensin permeates the central nervous system, stimulating sympathetic activity at the level of the fourth ventricle (such as the area postrema or nucleus of the tractus solitarius). However, sympathectomy in the rat with the use of 6-hydroxydopamine does not prevent the slow pressor effect in rats.16 There are no signs of sympathetic overactivity during angiotensin II infusion in dogs17 or men.18 Taken together, these findings argue against a significant role for the central nervous system in the slow pressor responses of angiotensin II.
The ability of angiotensin to stimulate oxidative stress
was first recognized by Rajagopalan et al.19 However,
these investigators used a very large amount of angiotensin
(0.7 mg per animal) to produce hypertension in rats. If
angiotensin indeed stimulates oxidant production,
there is a likelihood for oxygen to quench NO, reducing its
concentration at the level of smooth muscle in peripheral
resistance vessels. Furthermore, the binding of oxygen to NO could form
potent oxidant substances such as peroxynitrites, which could oxidize
arachidonic acid with the formation of isoprostanes.
This substance has been reported to be one of the most sensitive
markers in reflecting increases in oxidative stress. Furthermore, these
compounds are powerful vasoconstrictors of isolated vascular smooth
muscle cells14 and particularly of the
preglomerular vasculature (leading to decreased
glomerular filtration rate) and also stimulate tubular
sodium reabsorption.20 These vasoconstrictor and
antinatriuretic effects are both frankly
prohypertensinogenic, suggesting that they may be potentially important
in generating and/or sustaining hypertension during chronic
angiotensin infusion.
The present study reveals that low doses of angiotensin
II stimulate oxidative stress and consequently increase the free
isoprostane levels in circulating blood. Both free and total
isoprostanes are markers of oxidative stress. Isoprostanes are
initially formed in vivo esterified to tissue lipids, and subsequently
free isoprostanes are hydrolyzed and released into the systemic
circulation. Thus, it is tempting to speculate that they may be
involved in the slow pressor responses of angiotensin II.
Further studies are needed to establish a causative role rather than
merely a correlation between these compounds and the slow pressor
responses to angiotensin II. Finally, it should be noted
that oxidation also produces other forms of isoprostanes such as
isoprostane D and A2, which are also
vasoconstrictors. However, the F2 isoprostane
isoform is one of the more abundant isoforms in the circulation,
suggesting that it may be biologically important. However, it is
important to note that local concentrations may be quite different.
Conclusion
In conclusion, in the present study we found that infusion of
subpressor doses of angiotensin II into pigs causes blood
pressure to rise progressively. This increase in blood pressure is
accompanied by an increase in the circulating levels of free
isoprostanes. Whether isoprostane-induced vasoconstriction and
antinatriuresis play a role in the hypertensive responses in this model
remains to be established.
|
Acknowledgments |
|---|
This study was supported by National Institutes of Health grant HL-16496 and by the Mayo Foundation. The authors would like to thank John M. Stulak and Michael P. Stulak for technical assistance and Kristy J. Zodrow for secretarial assistance.
|
Footnotes |
|---|
Reprint requests to J. Carlos Romero, MD, Department of Physiology, Mayo Clinic, Rochester, MN 55905.
Received May 10, 1999; first decision June 4, 1999; accepted July 14, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Brown AJ, Casals-Stenzel J, Gofford S, Lever AF, Morton JJ. Comparison of fast and slow pressor effects of angiotensin II in the conscious rat. Am J Physiol. 1981;241:H381–H388.
2. Simon G, Abraham G, Cserep G. Pressor and subpressor angiotensin II administration: two experimental models of hypertension. Am J Hypertens. 1995;8:645–650.[Medline] [Order article via Infotrieve]
3. Dickinson CJ, Yu R. Mechanism involved in the progressive pressor response to very small amounts of angiotensin II. Circ Res. 1967;21(suppl II):II-157–II-163.
4. Lever AF. The fast and the slowly developing pressor effect of angiotensin II. In: Robertson JIS, Nicholls MG, eds. The Renin Angiotensin System. London, England: Gower Medical Publishing; 1993;28:1–28.9.
5.
DeClue JW, Guyton AC, Cowley AW Jr, Coleman TG, Norman
RA Jr, McCaa RE. Subpressor angiotensin infusion, renal
sodium handling, and salt-induced hypertension in the dog. Circ
Res. 1978;43:503–512.
6. Dowell FJ, Henrion D, Benessiano J, Poitevin P, Levy B. Chronic infusion of low-dose angiotensin II potentiates the adrenergic response in vivo. J Hypertens. 1996;14:177–182.[Medline] [Order article via Infotrieve]
7. Fink GD, Melaragno MG. Slow pressor effect of angiotensin II in normotensive rats with renal artery stenosis. Clin Exp Pharm Physiol. 1996;23:140–144.[Medline] [Order article via Infotrieve]
8.
Melaragno MG, Fink GD. Enhanced slow pressor effect of
angiotensin II in two-kidney, one clip rats.
Hypertension. 1995;25:288–293.
9.
Pueyo ME, Arnal J-F, Rami J, Michel J-B.
Angiotensin II stimulates the production of NO and
peroxynitrite in endothelial cells. Am J
Physiol. 1998;274:C214–C220.
10.
Pryor WA, Squadrito GL. The chemistry of peroxynitrite:
a product from the reaction of nitric oxide with superoxide.
Am J Physiol. 1995;268:L699–L722.
11. Morrow JD, Roberts LJ. The isoprostanes: current knowledge and directions for future research. Biochem Pharmacol. 1996;51:1–9.[Medline] [Order article via Infotrieve]
12. Roberts LJ II, Morrow JD. The generation and actions of isoprostanes. Biochim Biophys Acta. 1997;1345:121–135.[Medline] [Order article via Infotrieve]
13. Bolterman R, Krier J, Haas J, Lerman LO, Romero JC. Determination of plasma isoprostanes in normal pigs and in pigs with renal artery stenosis. FASEB J.. 1998;12:A91. Abstract.
14.
Morrow JD, Hill KE, Burk RF, Roberts LJ II. A series of
prostaglandin F2-like compounds are
produced in vivo and humans by a
non-cyclooxygenase, free radical-catalyzed
mechanism. Proc Natl Acad Sci U S A. 1990;87:9383–9387.
15. Bean BL, Brown JJ, Casals-Stenzel J, Fraser R, Lever AF, Miller JA, Morton JJ. The relation of arterial pressure and plasma angiotensin II concentration: a change produced by prolonged infusion of angiotensin II in the conscious dog. Circ Res. 1979;44:152–158.
16.
Li P, Jackson ED. Enhanced slow-pressor response
to angiotensin II in spontaneously hypertensive rats.
J Pharmacol Exp Ther. 1989;251:909–921.
17.
Carrol RG, Lohmeiser TG, Brown AJ. Chronic
angiotensin II infusion decreases renal
norepinephrine overflow in conscious dogs.
Hypertension. 1984;6:675–681.
18.
Goldsmith SR, Hasking FJ. Subpressor
angiotensin II infusions do not stimulate sympathetic
activity in humans. Am J Physiol. 1990;258:H179–H182.
19. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;8:1916–1923.
20.
Takahashi K, Nammou TM, Fukunaga M, Ebert J, Morrow JD,
Roberts LJ, Hoover RL, Badr KF. Glomerular actions of a
free radical-generated novel prostaglandin,
8-epi-prostaglandin F2 in the rat.
J Clin Invest. 1992;90:136–141.
This article has been cited by other articles:
 |
|
 |
|
  L. J. Janssen Isoprostanes and Lung Vascular Pathology Am. J. Respir. Cell Mol. Biol., October 1, 2008; 39(4): 383 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Z. Haque and D. S. A. Majid Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91phox subunit of NAD(P)H oxidase Am J Physiol Renal Physiol, September 1, 2008; 295(3): F758 - F764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Fujihara, G. R. Antunes, A. L. Mattar, D. M. A. C. Malheiros, J. M. Vieira Jr., and R. Zatz Chronic inhibition of nuclear factor-{kappa}B attenuates renal injury in the 5/6 renal ablation model Am J Physiol Renal Physiol, January 1, 2007; 292(1): F92 - F99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Laffer, R. J. Bolterman, J. C. Romero, and F. Elijovich Effect of Salt on Isoprostanes in Salt-Sensitive Essential Hypertension Hypertension, March 1, 2006; 47(3): 434 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Versari, E. Daghini, M. Rodriguez-Porcel, K. Sattler, O. Galili, K. Pilarczyk, C. Napoli, L. O. Lerman, and A. Lerman Chronic Antioxidant Supplementation Impairs Coronary Endothelial Function and Myocardial Perfusion in Normal Pigs Hypertension, March 1, 2006; 47(3): 475 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Campese, Y. Shaohua, and Z. Huiquin Oxidative Stress Mediates Angiotensin II-Dependent Stimulation of Sympathetic Nerve Activity Hypertension, September 1, 2005; 46(3): 533 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. A. Majid, A. Nishiyama, K. E. Jackson, and A. Castillo Superoxide scavenging attenuates renal responses to ANG II during nitric oxide synthase inhibition in anesthetized dogs Am J Physiol Renal Physiol, February 1, 2005; 288(2): F412 - F419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Welch, J. Blau, H. Xie, T. Chabrashvili, and C. S. Wilcox Angiotensin-induced defects in renal oxygenation: role of oxidative stress Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H22 - H28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Z. Haque and D. S. A. Majid Assessment of Renal Functional Phenotype in Mice Lacking gp91PHOX Subunit of NAD(P)H Oxidase Hypertension, February 1, 2004; 43(2): 335 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wang, Y. Chen, T. Chabrashvili, S. Aslam, L. J. Borrego Conde, J. G. Umans, and C. S. Wilcox Role of Oxidative Stress in Endothelial Dysfunction and Enhanced Responses to Angiotensin II of Afferent Arterioles from Rabbits Infused with Angiotensin II J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2783 - 2789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Sedeek, M. T. Llinas, H. Drummond, L. Fortepiani, S. R. Abram, B. T. Alexander, J. F. Reckelhoff, and J. P. Granger Role of Reactive Oxygen Species in Endothelin-Induced Hypertension Hypertension, October 1, 2003; 42(4): 806 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Pu, M. F. Neves, A. Virdis, R. M. Touyz, and E. L. Schiffrin Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling Hypertension, July 1, 2003; 42(1): 49 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Reckelhoff and J. C. Romero Role of oxidative stress in angiotensin-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R893 - R912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G G Koliakos, A G P Konstas, U Schlotzer-Schrehardt, G Hollo, I E Katsimbris, N Georgiadis, and R Ritch 8-Isoprostaglandin F2a and ascorbic acid concentration in the aqueous humour of patients with exfoliation syndrome Br J Ophthalmol, March 1, 2003; 87(3): 353 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F. Lopes, K. L. Martin, K. Nashar, J. D. Morrow, T. L. Goodfriend, and B. M. Egan DASH Diet Lowers Blood Pressure and Lipid-Induced Oxidative Stress in Obesity Hypertension, March 1, 2003; 41(3): 422 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Shokoji, A. Nishiyama, Y. Fujisawa, H. Hitomi, H. Kiyomoto, N. Takahashi, S. Kimura, M. Kohno, and Y. Abe Renal Sympathetic Nerve Responses to Tempol in Spontaneously Hypertensive Rats Hypertension, February 1, 2003; 41(2): 266 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. S. Gragasin, Y. Xu, I. A. Arenas, N. Kainth, and S. T. Davidge Estrogen Reduces Angiotensin II-Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 38 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kawada, E. Imai, A. Karber, W. J. Welch, and C. S. Wilcox A Mouse Model of Angiotensin II Slow Pressor Response: Role of Oxidative Stress J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2860 - 2868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Minuz, P. Patrignani, S. Gaino, M. Degan, L. Menapace, R. Tommasoli, F. Seta, M. L. Capone, S. Tacconelli, S. Palatresi, et al. Increased Oxidative Stress and Platelet Activation in Patients With Hypertension and Renovascular Disease Circulation, November 26, 2002; 106(22): 2800 - 2805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Krier, M. Rodriguez-Porcel, P. J. M. Best, J. C. Romero, A. Lerman, and L. O. Lerman Vascular responses in vivo to 8-epi PGF2alpha in normal and hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R303 - R308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Janssen and T. Tazzeo Involvement of TP and EP3 Receptors in Vasoconstrictor Responses to Isoprostanes in Pulmonary Vasculature J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1060 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Aizawa, N. Ishizaka, S.-I. Usui, N. Ohashi, M. Ohno, and R. Nagai Angiotensin II and Catecholamines Increase Plasma Levels of 8-Epi-Prostaglandin F2{alpha} With Different Pressor Dependencies in Rats Hypertension, January 1, 2002; 39(1): 149 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Role of Angiotensin II and Free Radicals in Blood Pressure Regulation in a Rat Model of Renal Hypertension Hypertension, September 1, 2001; 38(3): 361 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Ortiz, M. C. Manriquez, J. C. Romero, and L. A. Juncos Antioxidants Block Angiotensin II-Induced Increases in Blood Pressure and Endothelin Hypertension, September 1, 2001; 38(3): 655 - 659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Janssen Isoprostanes: an overview and putative roles in pulmonary pathophysiology Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1067 - L1082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Halvorsen, A. C. Staff, T. Henriksen, T. Sawamura, and T. Ranheim 8-iso-Prostaglandin F2{{alpha}} Increases Expression of LOX-1 in JAR Cells Hypertension, April 1, 2001; 37(4): 1184 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rodriguez-Porcel, A. Lerman, P. J. M. Best, J. D. Krier, C. Napoli, and L. O. Lerman Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity J. Am. Coll. Cardiol., February 1, 2001; 37(2): 608 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. A. Mervaala, Z. J. Cheng, I. Tikkanen, R. Lapatto, K. Nurminen, H. Vapaatalo, D. N. Muller, A. Fiebeler, U. Ganten, D. Ganten, et al. Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes Hypertension, February 1, 2001; 37(2): 414 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. O. Lerman, K. A. Nath, M. Rodriguez-Porcel, J. D. Krier, R. S. Schwartz, C. Napoli, and J. C. Romero Increased Oxidative Stress in Experimental Renovascular Hypertension Hypertension, February 1, 2001; 37(2): 541 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, M. J. Davies, S. D. Schriver, T. J. Lauterio, and R. L. Prewitt Oxidative Stress in a Rat Model of Obesity-Induced Hypertension Hypertension, February 1, 2001; 37(2): 554 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nishiyama, T. Fukui, Y. Fujisawa, M. Rahman, R.-X. Tian, S. Kimura, and Y. Abe Systemic and Regional Hemodynamic Responses to Tempol in Angiotensin II-Infused Hypertensive Rats Hypertension, January 1, 2001; 37(1): 77 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yamamoto, T. Masuyama, Y. Sakata, T. Mano, N. Nishikawa, H. Kondo, N. Akehi, T. Kuzuya, T. Miwa, and M. Hori Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts Cardiovasc Res, August 1, 2000; 47(2): 274 - 283. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||